Retroviruses are a relatively newly recognized group of RNA viruses. Many are associated with malignancies in mammals. The first retrovirus to be isolated, RNA tumor virus, was isolated by Rous early in this century. However, it was several decades later before it was realized that retroviruses play an important role in oncology. Pioneering work in this area included the isolation of retroviruses in laboratory mice and their subsequent linkage to murine leukemias and lymphomas (Gross, L. [Ed.] 1983, Oncogenic Viruses. Pergamon Press, N.Y.). Exogenous retroviruses are now linked to human malignancies, indicating that some types of cancer are infectious (Gallo, R. C.; [1984] Gallo, R. C., Essex, M. E. and Gross L. [Eds] Human T-Cell Leukemia/Lymphoma Virus--The Family of Human T-Lymphotropic Retroviruses: Their Role in Malignancies and Association with AIDS. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.). In addition, acquired immune deficiency syndrome (AIDS) is now linked to an infectious retrovirus.
AIDS is a disease that was first described in mid 1981. By Aug. 30, 1985, 12,932 cases had been reported in the United States, with 6,480 deaths. Reliable estimates suggest that as many as one million Americans have been infected with the AIDS virus to date. (Curran et al. [1985] Science 229:1352-1357). Retrovirus infections usually persist for life. The severity of this disease has placed it at the top of the health priorities of the U.S. Research on AIDS has been successful in linking this disease to a virus, human T-cell lymphotropic virus type III (HTLV-III) and to the HTLV genome itself, rather than to a minor component of the virus complex. See Gallo, R. C. et al. (1983) Science 220:865-867 and Fisher et al. (1985) Nature 316:262-265. This virus is transmitted through sexual contact, sharing contaminated needles, through blood and blood products and from infected mothers to their newborn children. Although 73% of the cases are reported as occurring in homosexual men, the number of cases diagnosed in heterosexuals is increasing rapidly. An immunodiagnostic test has been developed to detect the presence of antibodies to HTLV-III. This test has been used to detect antibody in over 90% of AIDS patients and from a high proportion of people in high-risk groups. Through the modes of infection listed above, the number of cases is expected to increase. Therefore, an epidemic is developing that could kill most of its victims.
A two-pronged strategy is being taken to treat or cure AIDS: to inhibit the virus and to build up the immune system. Research is being undertaken on developing a vaccine, although it is unknown at this time whether a safe and effective vaccine can be developed. Antiviral drugs are also being sought which would inhibit the virus or prevent infection. Dolin (Dolin, R. [1985] Science 227:1296-1303) recently reviewed the successful development of compounds for antiviral chemotherapy and chemoprophylaxis. These compounds, such as nucleoside analogs, typically block some part of the life cycle of a virus. These agents are specifically activated and incorporated by viral enzymes but are poor substrates for cellular enzymes. Therefore, these drugs interfere with viral DNA replication while not affecting the DNA replication of the host cells. Several drugs have been investigated to treat AIDS, including suramin, Fascarnet and HPA 23. The former two are antiviral drugs used for other viruses while the last is a newly developed French drug. Although these drugs may inhibit virus replication in the body, they also have hazardous side effects.
There has recently been increased interest in searching for pharmaceuticals from marine macroalgae. Hoppe et al. (Hoppe, O., Levring, T. and Tanaka, Y. [1978] Marine Algae in Pharmaceutical Science. W. de Gruyter, N.Y.) published a volume that reviews many of the established or potential pharmaceutical uses of marine algae. It is apparent from the papers in this book and the large volume of literature that is cited that there are many potential uses that are yet untapped. More recently, Fenical (Fenical, W. [1983] Proceedings of the Joint U.S.-China Phycological Symposium, Quingdao, China, 1981, Academia Sinica, Peoples' Republic of China) reviewed the potential for the use of marine algae as the source of pharmaceuticals and agrichemicals. Efforts have been directed at studying marine algae with antiviral activity (Ehresmann, D. W., et al. [1977] J. Phycol. 13:37-40, and Blunden, G. et al. [1981] Bot. Marina 24:267-272), with antibiotic activity (Faulkner, D. J. [1978] P. Sammes [Ed.] Topics in Antibiotic Chemistry. E. Horwod Publishers, Chichester, England, and Shield, L. S. and Rinehart, K. L. Jr. [1978] Antibiotics, Isolation, Separation and Purification. Journal of Chromatography Library, Elsevier, N.Y.), and with unique and specific cytotoxicity (Gerwick, W. H. et al. [1980] J. Amer. Chem. Soc. 102:7991-7993).
Marine algae have been screened for activity against herpes simplex virus (HSV, Ehresmann, D. W. et al. [1977] J. Phycol. 13:37-40) and influenza virus (Blunden, G. et al. [1981] Bot. Marina 24:267-272). Deig et al. (Deig, E. F. et al. [1974] Antimicrob. Ag. Chemother. 6:524-525) first reported that in vitro replication of HSV was inhibited by extracts of several marine red algae. Twenty-eight species of marine macroalgae were collected and extracts from these red algae were tested for antiviral activity (Ehresmann, D. W. et al. [1977] J. Phycol. 13:37-40). Ten of these reduced the infectiousness of HSV types 1 and 2. Studies of these extracts indicated that the active agent was a structural polysaccharide which blocked an early step in the cycle of infection, thereby restricting the spread of the virus (Ehresmann, D. W. et al. [1977] J. Phycol. 13:37-40; Hatch, M. T. et al. [1979] O. Hoppe, T. Levring and Y. Tanaka [Eds] Marine Algae in Pharmaceutical Science. W. de Gruyter, N.Y.). Richards et al. (Richards, J. T. et al. (1978) Antimicrob. Agents Chemother. 14:24-30) have shown that extracts of two red algae have in vivo antiviral activity in mice infected with herpes simplex virus. This research has spawned sufficient interest for several patents. Three patents have been issued for red algal treatments of herpes virus infections (U.S. Pat. Nos. 4,162,308 and 4,162,309, issued 1979 and 4,522,814, issued 1985). They claim that these red algae have shown effective treatment in humans. There is no known prior art which discloses the isolation of anti-AIDS, or anti-retroviral activity from marine algae.
In parent application Ser. No. 801,115, abandoned, I disclose and claim a novel composition of matter designated as SA-1. This material has a high degree of activity against the virus HTLV-III. Accordingly, SA-1 can be used to treat AIDS and other infections caused by retroviruses.
SA-1 is disclosed in Ser. No. 801,115 as being obtained from the well-known marine algae genus Schizymenia.
Further work on SA-1, which is now referred to as HIVA (human-immunodeficiency-antiviral), reveals that this material contains the well-known sulfated polysaccharide, carrageenan. Tests have now shown that decreasing concentrations of carrageenan correlate with decreasing levels of reverse-transcriptase inhibition using a standard test as disclosed in Ser. No. 801,115.